There is a critical need for the correct diagnosis and treatment of depression in bipolar disorder - I (BD-Dep). BD is a devastating illness with a lifetime prevalence of 1%, and depression is the most common and most frequent presenting episode type, and is associated with a high risk of suicide. No marker has been identified that distinguishes the depression of BD from that of major depressive disorder (MDD-Dep). Individuals with BD may receive treatments designed for MDD that may have negative consequences, and currently available treatments for BD-Dep are limited in effectiveness and can have adverse effects. These factors highlight the critical importance of identifying a new mechanism that distinguishes BD-Dep from MDD-Dep and that could serve as a target for novel treatment strategies for BD- Dep. Convergent functional magnetic resonance imaging (fMRI) evidence supports a central role in BD for the ventral prefrontal cortex (vPFC), an important region for regulation of emotions and impulses, which are significantly impaired in individuals with BD. Evidence suggests particular abnormalities of responses in the vPFC, and in its regulation of limbic structures such as the amygdala, during the processing of positive emotional stimuli in BD, not evident in MDD. Recent evidence points to glutamatergic system abnormalities in the vPFC specific to BD, with magnetic resonance spectroscopy studies showing different glutamate levels in BD-Dep than in MDD-Dep. Postmortem research supports the specific involvement of PFC metabotropic glutamatergic receptors (mGluR5) in BD-Dep. Our exciting new pilot data from in vivo measurement of mGluR5 using positron emission tomography (PET) provide preliminary evidence for vPFC mGluR5 involvement in BD-Dep, but not MDD-Dep, supporting mGluR5 as a biomarker to help differentiate and diagnose BD-Dep and as a potential novel treatment target. Moreover, we observed associations between the PET and fMRI findings, as well as relationships of those measures to deficits in executive control and impulse regulation. We propose a multidisciplinary PET, fMRI and behavioral study comparing 40 individuals with BD- Dep to 40 with MDD-Dep and 40 healthy comparison (HC) individuals to identify differences in vPFC mGluR5 levels and determine whether they may underlie functional differences between BD-Dep and MDD-Dep, and serve as a biomarker to differentiate them. It is hypothesized that vPFC mGluR5 will be lower in the BD-Dep group, as compared to the MDD-Dep and HC groups. It is also hypothesized that vPFC functional activation and connectivity during processing of positive emotional faces will be reduced in BD-Dep group, as compared to MDD-Dep and HC groups. Finally, it is hypothesized that the lower mGluR5 availability in BD-Dep will be significantly associated with the vPFC dysfunction, as well as behaviors reflecting impaired vPFC system regulation. These results may lead to a breakthrough in characterization and differentiation of BD-Dep from MDD-Dep, as well as to the development of more specifically targeted and efficacious treatments for BD-Dep.